CH642378A5 - NEW PARACETAMOL DERIVATIVE, ITS PREPARATION PROCESS AND ITS USE IN THERAPEUTICS. - Google Patents
NEW PARACETAMOL DERIVATIVE, ITS PREPARATION PROCESS AND ITS USE IN THERAPEUTICS. Download PDFInfo
- Publication number
- CH642378A5 CH642378A5 CH1073879A CH1073879A CH642378A5 CH 642378 A5 CH642378 A5 CH 642378A5 CH 1073879 A CH1073879 A CH 1073879A CH 1073879 A CH1073879 A CH 1073879A CH 642378 A5 CH642378 A5 CH 642378A5
- Authority
- CH
- Switzerland
- Prior art keywords
- phosphate
- acetaminophenyl
- salt
- paracetamol
- disodium salt
- Prior art date
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical class CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000003814 drug Substances 0.000 title 1
- PSQWZQGQIUGIRU-UHFFFAOYSA-N (4-acetamidophenyl) dihydrogen phosphate Chemical compound CC(=O)NC1=CC=C(OP(O)(O)=O)C=C1 PSQWZQGQIUGIRU-UHFFFAOYSA-N 0.000 claims description 18
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 230000000202 analgesic effect Effects 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- 229960005489 paracetamol Drugs 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 150000003838 adenosines Chemical class 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 230000020477 pH reduction Effects 0.000 claims description 3
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- 230000000397 acetylating effect Effects 0.000 claims description 2
- 229960005305 adenosine Drugs 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 150000002333 glycines Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 3
- 239000000730 antalgic agent Substances 0.000 claims 2
- 239000002221 antipyretic Substances 0.000 claims 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- 206010020843 Hyperthermia Diseases 0.000 claims 1
- XAHQYEAIJGTPET-JEDNCBNOSA-N [(1s)-5-amino-1-carboxypentyl]azanium;dihydrogen phosphate Chemical compound OP(O)([O-])=O.NCCCC[C@H]([NH3+])C(O)=O XAHQYEAIJGTPET-JEDNCBNOSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000001647 drug administration Methods 0.000 claims 1
- 239000000796 flavoring agent Substances 0.000 claims 1
- 235000019634 flavors Nutrition 0.000 claims 1
- 150000002334 glycols Chemical class 0.000 claims 1
- 230000036031 hyperthermia Effects 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 claims 1
- 230000007928 solubilization Effects 0.000 claims 1
- 238000005063 solubilization Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 206010037660 Pyrexia Diseases 0.000 description 6
- 230000001754 anti-pyretic effect Effects 0.000 description 6
- 230000027950 fever generation Effects 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- -1 amino acid salts Chemical class 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000007059 acute toxicity Effects 0.000 description 4
- 231100000403 acute toxicity Toxicity 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000219995 Wisteria Species 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VHRDVBFFZCBVAL-UHFFFAOYSA-N (2-aminophenyl) dihydrogen phosphate Chemical compound NC1=CC=CC=C1OP(O)(O)=O VHRDVBFFZCBVAL-UHFFFAOYSA-N 0.000 description 1
- YRGZCCSQCZFLQO-UHFFFAOYSA-N (4-nitrophenyl) dihydrogen phosphate;hexahydrate Chemical compound O.O.O.O.O.O.OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 YRGZCCSQCZFLQO-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ZYPZVOKVDNSKLP-UHFFFAOYSA-N tris(4-aminophenyl) phosphate Chemical compound C1=CC(N)=CC=C1OP(=O)(OC=1C=CC(N)=CC=1)OC1=CC=C(N)C=C1 ZYPZVOKVDNSKLP-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
La présente invention concerne un nouveau dérivé du paracétamol particulièrement bien soluble dans l'eau, permettant d'obtenir des concentrations importantes de principe actif, sans apport d'adjuvants, pouvant être donc facilement utilisé pour une administration parentérale, par voie intramusculaire ou intraveineuse, ainsi que pour une administration orale nécessitant une mise en solution dans l'eau telle que, par exemple, dans l'utilisation des formes sachets. The present invention relates to a new paracetamol derivative which is particularly well soluble in water, making it possible to obtain high concentrations of active principle, without the addition of adjuvants, which can therefore be easily used for parenteral administration, by intramuscular or intravenous route, as well as for oral administration requiring dissolution in water such as, for example, in the use of sachet forms.
Le produit de l'invention a montré, lors de l'expérimentation pharmacologique chez l'animal, des propriétés analgésique et antipyrétique tout à fait comparables à celles du paracétamol, ce qui permet son utilisation chez l'homme dans le traitement de toutes les h3c-c-nh-0 The product of the invention has shown, during pharmacological experimentation in animals, analgesic and antipyretic properties quite comparable to those of paracetamol, which allows its use in humans in the treatment of all h3c -c-nh-0
(I) (I)
utilisé sous la forme de ses sels avec des bases minérales ou organi-15 ques convenables pour une utilisation thérapeutique. Les sels préférés selon l'invention sont le sel disodique, les sels d'aminoacides tels que la glycine, la lysine et le sel d'adénosine. used in the form of its salts with mineral or organic bases suitable for therapeutic use. The preferred salts according to the invention are the disodium salt, the amino acid salts such as glycine, lysine and the adenosine salt.
L'invention concerne également le procédé de préparation du sel disodique du phosphate de p-acétaminophényle qui consiste 1) à ré-20 duire le sel disodique de l'ester phosphorique du p-nitrophénol en le dérivé p-amino correspondant par hydrogénation en présence d'un catalyseur palladium sur charbon et 2) à acétyler ledit dérivé p-amino à l'aide d'anhydride acétique. The invention also relates to the process for preparing the disodium salt of p-acetaminophenyl phosphate which comprises 1) reducing the disodium salt of the phosphoric ester of p-nitrophenol to the corresponding p-amino derivative by hydrogenation in the presence a palladium on carbon catalyst and 2) acetylating said p-amino derivative using acetic anhydride.
L'invention concerne également le procédé pour l'obtention des 25 sels d'aminoacides du phosphate de p-acétaminophényle, qui consiste 1) à préparer le phosphate de p-acétaminophényle par acidification de son sel disodique et 2) à faire réagir, en quantités équimoléculaires, ledit ester-acide obtenu à l'étape 1) avec une amine, telle de la glycine, la lysine ou l'adénosine. The invention also relates to the process for obtaining the amino acid salts of p-acetaminophenyl phosphate, which consists of 1) preparing p-acetaminophenyl phosphate by acidification of its disodium salt and 2) reacting, equimolecular amounts, said ester-acid obtained in step 1) with an amine, such as glycine, lysine or adenosine.
30 Les modalités de la préparation sont indiquées dans les exemples ci-après: The preparation methods are indicated in the examples below:
Exemple 1: Example 1:
Première étape: Préparation du sel disodique de phosphate de p-35 aminophênyle. First step: Preparation of the disodium salt of p-35 aminophenyl phosphate.
On effectue l'hydrogénation à pression atmosphérique et température ambiante de 25 g de sel disodique du monophosphate de p-nitrophényle hexahydraté, dans 21 d'éthanol à 50%, en présence de 4 g de catalyseur palladium sur charbon à 5%. Après élimination du 40 catalyseur, on évapore à sec. The hydrogenation is carried out at atmospheric pressure and at room temperature of 25 g of disodium salt of p-nitrophenyl monophosphate hexahydrate, in 50% ethanol, in the presence of 4 g of 5% palladium on carbon catalyst. After removal of the catalyst, it is evaporated to dryness.
On reprend par l'éthanol absolu, on essore et sèche à 60° C pendant 4 h. On obtient environ 15 g de produit anhydre. It is taken up in absolute ethanol, filtered and dried at 60 ° C for 4 h. About 15 g of anhydrous product are obtained.
Deuxième étape: Préparation du sel disodique de phosphate de p-acètaminophènyle. Second step: Preparation of the disodium salt of p-acetaminophenyl phosphate.
45 Dans un ballon contenant 200 ml d'anhydride acétique, on ajoute peu à peu 15 g du sel disodique du phosphate de p-aminophé-nyle. Après agitation pendant 30 min, on ajoute 500 ml d'éther et on continue l'agitation pendant 30 min. 45 15 g of the disodium salt of p-aminophenyl phosphate are gradually added to a flask containing 200 ml of acetic anhydride. After stirring for 30 min, 500 ml of ether are added and stirring is continued for 30 min.
On ajoute au précipité 250 ml d'acétone et 10 ml d'eau, et on 50 agite à nouveau 15 min. On essore, lave avec deux fois 450 ml d'acétone et on reprend par 150 ml d'éthanol. 250 ml of acetone and 10 ml of water are added to the precipitate, and the mixture is stirred again for 15 min. It is filtered, washed with twice 450 ml of acetone and taken up in 150 ml of ethanol.
Après abandon 12 h à température ambiante, on essore, lave avec deux fois 15 ml d'éthanol et sèche à 60° C. On obtient environ 13 g de produit brut qu'on redissout dans 60 ml d'eau et additionne 55 de 1,5 g de noir décolorant. Après filtration, on dilue le filtrat par 500 ml d'acétone. On agite et essore le sel disodique du phosphate de N-acétyl-p-aminophénol. Après plusieurs lavages par l'acétone, on sèche le produit 2 h à 60°C, puis toute une nuit à 105°C. After leaving for 12 h at room temperature, it is filtered, washed with twice 15 ml of ethanol and dried at 60 ° C. We obtain approximately 13 g of crude product which is redissolved in 60 ml of water and added 55 to 1 , 5 g of bleaching black. After filtration, the filtrate is diluted with 500 ml of acetone. The disodium salt of the N-acetyl-p-aminophenol phosphate is stirred and drained. After several washings with acetone, the product is dried for 2 h at 60 ° C., then overnight at 105 ° C.
On obtient environ 7,5 g de sel disodique sous forme de cristaux 60 incolores dont le point de fusion est supérieur à 265° C. Ce produit est très soluble dans l'eau instantanément à 50 g pour 100 ml à température ambiante. La solution est parfaitement stable et possède un pH neutre. About 7.5 g of disodium salt are obtained in the form of colorless crystals 60 whose melting point is above 265 ° C. This product is instantly soluble in water at 50 g per 100 ml at room temperature. The solution is perfectly stable and has a neutral pH.
65 Exemple 2: 65 Example 2:
On prépare le phosphate de p-acétaminophényle par acidification d'une solution aqueuse de son sel disodique. L'ester-acide ainsi séparé se présente sous forme de cristaux incolores contenant une The p-acetaminophenyl phosphate is prepared by acidification of an aqueous solution of its disodium salt. The acid ester thus separated is in the form of colorless crystals containing a
3 3
642 378 642,378
molécule d'eau par molécule de produit [F = 135°C (déshydratation); 205° C (produit anhydre)]. water molecule per product molecule [M = 135 ° C (dehydration); 205 ° C (anhydrous product)].
Le sel de glycine de phosphate de p-acétaminophényle est préparé par dissolution de quantités équimoléculaires de glycine et de l'ester-acide, dans l'eau à 25° C, suivie de précipitation à l'acétone et 5 de recristallisation dans l'éthanol à 85%. Il se présente sous forme de cristaux incolores de F = 195°C. The glycine salt of p-acetaminophenyl phosphate is prepared by dissolving equimolecular amounts of glycine and the acid ester in water at 25 ° C, followed by precipitation with acetone and recrystallization in 85% ethanol. It is in the form of colorless crystals of F = 195 ° C.
On prépare de la même façon le sel de lysine en utilisant l'éthanol au lieu de l'acétone pour la précipitation. Cristaux incolores de F = 179-181° C (capillaire Büchi). io The lysine salt is prepared in the same way using ethanol instead of acetone for precipitation. Colorless crystals of F = 179-181 ° C (Büchi capillary). io
Le sel d'adénosine, obtenu dans les mêmes conditions, précipite spontanément du milieu réactionnel sous la forme de monohydrate. Cristaux incolores de F = 163°C (capillaire Büchi). The adenosine salt, obtained under the same conditions, spontaneously precipitates from the reaction medium in the form of monohydrate. Colorless crystals of F = 163 ° C (Büchi capillary).
L'expérimentation pharmacologique a permis de mettre en évidence les propriétés analgésique et antipyrétique du phosphate de p- 15 acétaminophényle et de ses sels, qui sont tout à fait comparables à celles du paracétamol, avec une toxicité du même ordre. Pharmacological experimentation has made it possible to demonstrate the analgesic and antipyretic properties of p-acetaminophenyl phosphate and its salts, which are quite comparable to those of paracetamol, with a toxicity of the same order.
Sel disodique du phosphate de p-acétaminophényle Disodium salt of p-acetaminophenyl phosphate
1) Toxicité aiguë 20 1) Acute toxicity 20
La DL50 déterminée par voie orale chez la souris est de l'ordre de 1200 mg/kg, ce qui équivaut à celle du paracétamol sur une base équimoléculaire. The LD50 determined orally in mice is of the order of 1200 mg / kg, which is equivalent to that of paracetamol on an equimolecular basis.
2) Activité analgésique 2) Analgesic activity
Elle est déterminée d'après le test de Koster R. et coll. («Fed. 25 Proc.», 1959,18,412) qui consiste à injecter 0,5 ml I.P. d'acide acétique à 0,5% à la souris et à compter le nombre de contorsions pendant les 10 min suivantes; l'effet analgésique du produit selon l'invention administré par voie orale 1 h avant le test est révélé par la diminution en pourcentage du nombre de contorsions par rapport aux témoins. It is determined according to the test by Koster R. et al. (“Fed. 25 Proc.”, 1959,18,412) which consists in injecting 0.5 ml I.P. of 0.5% acetic acid into the mouse and counting the number of contortions during the following 10 min; the analgesic effect of the product according to the invention administered orally 1 h before the test is revealed by the reduction in percentage of the number of contortions compared to the controls.
Dose mg/kg Dose mg / kg
Activité Activity
Produit de l'invention (sel disodique) Product of the invention (disodium salt)
275 (= 1 mmol) 275 (= 1 mmol)
54% 54%
Paracétamol Paracetamol
150 (=1 mmol) 150 (= 1 mmol)
52% 52%
3) Activité antipyrétique 3) Antipyretic activity
Elle est déterminée selon le test de Winder et coll. (« J. Pharm, exp. Therap.», 1961,133,117) qui consiste à suivre l'évolution de la température chez des rats témoins et des rats traités, pendant 4 h, après administration sous-cutanée d'un agent pyrogène (à base de levure de bière). It is determined according to the test of Winder et al. (“J. Pharm, exp. Therap.”, 1961, 133, 117) which consists in monitoring the temperature evolution in control rats and in treated rats, for 4 h, after subcutaneous administration of a pyrogenic agent ( brewer's yeast).
L'activité est déterminée pour les voies d'administration orale, intrapéritonéale et intraveineuse aux doses indiquées dans le tableau ci-dessous. ^ The activity is determined for the oral, intraperitoneal and intravenous routes of administration at the doses indicated in the table below. ^
Temps Time
Lots Lots
0 0
'Ah lh 'Ah lh
2 h 2 hrs
3 h 3 hrs
4h 4h
Témoin pyrexie Pyrexia witness
39,1 °C 39.1 ° C
39,3 °C 39.3 ° C
39,1 °C 39.1 ° C
39 °C 39 ° C
38,9 °C 38.9 ° C
38,7 °C 38.7 ° C
Paracétamol 150 mg/kg (1 mmol) par voie orale Paracetamol 150 mg / kg (1 mmol) orally
39,1 °C 39.1 ° C
38,1 °C 38.1 ° C
37,7 °C 37.7 ° C
37 °C 37 ° C
37 °C 37 ° C
37,6 °C 37.6 ° C
Produit de l'invention (sel disodique) 275 mg/kg (1 mmol) par voie orale Product of the invention (disodium salt) 275 mg / kg (1 mmol) orally
39,2 °C 39.2 ° C
38,2 °C 38.2 ° C
37,5 °C 37.5 ° C
36,8 °C 36.8 ° C
37,3 °C 37.3 ° C
38,3 °C 38.3 ° C
Sel disodique 275 mg/kg par voie I.P. Disodium salt 275 mg / kg I.P.
39,2 °C 39.2 ° C
38,3 °C 38.3 ° C
37,6 °C 37.6 ° C
37 °C 37 ° C
36,9 °C 36.9 ° C
38,1 °C 38.1 ° C
Sel disodique 100 mg/kg par voie I.V. Disodium salt 100 mg / kg I.V.
39 °C 39 ° C
38,3 °C 38.3 ° C
37,8 °C 37.8 ° C
37,7 °C 37.7 ° C
38,4 °C 38.4 ° C
— -
Sel de glycine du phosphate de p-acétaminophényle (PM 306) 1) Activité analgésique (souris) P-acetaminophenyl phosphate glycine salt (PM 306) 1) Analgesic activity (mouse)
Par voie orale, la dose active 50 (dose pour laquelle on a une activité de 50% = DA50) est de 520 mg/kg. Orally, the active dose 50 (dose for which there is an activity of 50% = DA50) is 520 mg / kg.
2) Activité antipyrétique (rats) 2) Antipyretic activity (rats)
La dose administrée est de 1 mmol, soit 306 mg/kg. Les résultats obtenus (températures) sont donnés dans les tableaux suivants: The administered dose is 1 mmol, or 306 mg / kg. The results obtained (temperatures) are given in the following tables:
Par voie orale: Orally:
Temps Time
Lots Lots
0 0
'Ah lh l'A h 'Ah lh A h
2 h 2 hrs
3 h 3 hrs
4h 4h
Témoin absolu Absolute witness
37,6 °C 37.6 ° C
38 °C 38 ° C
37,9 °C 37.9 ° C
38 °C 38 ° C
38 °C 38 ° C
37,4 °C 37.4 ° C
37,2 °C 37.2 ° C
Témoin pyrexie Pyrexia witness
38,8 °C 38.8 ° C
39,1 °C 39.1 ° C
39,2 °C 39.2 ° C
39,2 °C 39.2 ° C
39,1 °C 39.1 ° C
38,9 °C 38.9 ° C
38,8 °C 38.8 ° C
Sel de glycine Wisteria salt
38,9 °C 38.9 ° C
38,8 °C 38.8 ° C
38 °C 38 ° C
37,7 °C 37.7 ° C
37,5 °C 37.5 ° C
37,7 °C 37.7 ° C
38,6 °C 38.6 ° C
642 378 642,378
4 4
Par voie intraveineuse: Intravenously:
Temps Time
Lots Lots
0 0
V4 h V4 h
1 h 1 hr
1 Vi h 1 Vi h
2h 2h
3 h 3 hrs
4 h 4 hrs
Témoin absolu Absolute witness
37,1 °C 37.1 ° C
38,4 °C 38.4 ° C
38,1 °C 38.1 ° C
38 °C 38 ° C
37,7 °C 37.7 ° C
37,7 °C 37.7 ° C
37,4 °C 37.4 ° C
Témoin pyrexie Pyrexia witness
38,6 °C 38.6 ° C
39,6 °C 39.6 ° C
39,8 °C 39.8 ° C
39,2 °C 39.2 ° C
39,2 °C 39.2 ° C
38,5 °C 38.5 ° C
38,3 °C 38.3 ° C
Sel de glycine Wisteria salt
38,8 °C 38.8 ° C
38,6 °C 38.6 ° C
37,8 °C 37.8 ° C
37,5 °C 37.5 ° C
37,2 °C 37.2 ° C
38,1 °C 38.1 ° C
39,0 °C 39.0 ° C
3) Toxicité aiguë (DLS0) (souris) 3) Acute toxicity (DLS0) (mouse)
Par voie orale, la DL50 est de 1850 mg/kg (6,04 mmol/kg). The oral LD50 is 1850 mg / kg (6.04 mmol / kg).
Sel de lysine du phosphate de p-acétaminophényle 1) Activité analgésique (souris) L-salt of p-acetaminophenyl phosphate 1) Analgesic activity (mouse)
Par voie orale, la DAS0 est de 625 mg/kg. The oral DAS0 is 625 mg / kg.
2) Activité antipyrétique (rats) 2) Antipyretic activity (rats)
15 La dose administrée était de 377 mg/kg (1 mmol/kg). Les résultats sont donnés dans les tableaux ci-dessous. The dose administered was 377 mg / kg (1 mmol / kg). The results are given in the tables below.
Par voie orale: Orally:
Temps Time
Lots Lots
0 0
Vi h lh lVih Vi h lh lVih
2 h 2 hrs
3 h 3 hrs
4h 4h
Témoin absolu Absolute witness
37,6 °C 37.6 ° C
38 °C 38 ° C
37,9 °C 37.9 ° C
38 °C 38 ° C
38 °C 38 ° C
37,4 °C 37.4 ° C
37,2 °C 37.2 ° C
Témoin pyrexie Pyrexia witness
38,8 °C 38.8 ° C
39,1 °C 39.1 ° C
39,2 °C 39.2 ° C
39,2 °C 39.2 ° C
39,1 °C 39.1 ° C
38,9 °C 38.9 ° C
38,8 °C 38.8 ° C
Sel de lysine Lysine salt
38,9 °C 38.9 ° C
38,7 °C 38.7 ° C
38 °C 38 ° C
37,3 °C 37.3 ° C
37,2 °C 37.2 ° C
37,7 °C 37.7 ° C
38 °C 38 ° C
Par voie intraveineuse: Intravenously:
Temps Time
Lots Lots
0 0
Vi h lh Vi h lh
1 Vi h 1 Vi h
2h 2h
3 h 3 hrs
4h 4h
Témoin absolu Absolute witness
37,1 °C 37.1 ° C
38,4 °C 38.4 ° C
38,1 °C 38.1 ° C
38 °C 38 ° C
37,7 °C 37.7 ° C
37,7 °C 37.7 ° C
37,4 °C 37.4 ° C
Témoin pyrexie Pyrexia witness
38,6 °C 38.6 ° C
39,6 °C 39.6 ° C
39,8 °C 39.8 ° C
39,2 °C 39.2 ° C
39,2 °C 39.2 ° C
38,5 °C 38.5 ° C
38,3 °C 38.3 ° C
Sel de lysine Lysine salt
38,8 °C 38.8 ° C
38,6 °C 38.6 ° C
37,8 °C 37.8 ° C
37,5 °C 37.5 ° C
37,2 °C 37.2 ° C
38,1 °C 38.1 ° C
39,0 °C 39.0 ° C
3) Toxicité aiguë (DLS0) (souris) 3) Acute toxicity (DLS0) (mouse)
Par voie orale, la DL50 est de 1875 mg/kg (4,97 mmol/kg). The oral LD50 is 1875 mg / kg (4.97 mmol / kg).
45 45
Sel d'adénosine du phosphate de p-acétaminophényle 1) Activité analgésique (souris) Adenosine salt of p-acetaminophenyl phosphate 1) Analgesic activity (mouse)
Par voie orale, la DA50 est de 920 mg/kg. Orally, the DA50 is 920 mg / kg.
2) Activité antipyrétique (rats) 2) Antipyretic activity (rats)
La dose administrée par voie orale était de 498 mg/kg, soit 1 mmol/kg. Les résultats sont donnés dans le tableau ci-dessous: The oral dose was 498 mg / kg, or 1 mmol / kg. The results are given in the table below:
Temps Time
Lots Lots
0 0
Vi h lh Vi h lh
1 Vi h 1 Vi h
2h 2h
3 h 3 hrs
4h 4h
Témoin absolu Absolute witness
37,6 °C 37.6 ° C
38,0 °C 38.0 ° C
38,0 °C 38.0 ° C
38,0 "C 38.0 "C
38,1 °C 38.1 ° C
37,2 °C 37.2 ° C
37,3 °C 37.3 ° C
Témoin pyrexie Pyrexia witness
38,9 °C 38.9 ° C
39,2 °C 39.2 ° C
39,0 °C 39.0 ° C
38,8 °C 38.8 ° C
38,7 °C 38.7 ° C
38,8 °C 38.8 ° C
38,9 °C 38.9 ° C
Sel d'adénosine Adenosine salt
39,0 °C 39.0 ° C
37,7 °C 37.7 ° C
36,9 °C 36.9 ° C
36,7 °C 36.7 ° C
36,8 °C 36.8 ° C
37,6 °C 37.6 ° C
38,3 °C 38.3 ° C
3) Toxicité aiguë (DL50) (souris) 3) Acute toxicity (LD50) (mouse)
Par voie orale, la DLS0 est de 2620 mg/kg (5,26 mmol/kg). The oral LDS0 is 2620 mg / kg (5.26 mmol / kg).
R R
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7835429A FR2444043A1 (en) | 1978-12-15 | 1978-12-15 | NEW PARACETAMOL DERIVATIVE, PREPARATION METHOD THEREOF AND THERAPEUTIC USE THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH642378A5 true CH642378A5 (en) | 1984-04-13 |
Family
ID=9216203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1073879A CH642378A5 (en) | 1978-12-15 | 1979-12-04 | NEW PARACETAMOL DERIVATIVE, ITS PREPARATION PROCESS AND ITS USE IN THERAPEUTICS. |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US4322410A (en) |
| JP (1) | JPS5583792A (en) |
| BE (1) | BE880615A (en) |
| CA (1) | CA1131627A (en) |
| CH (1) | CH642378A5 (en) |
| DE (1) | DE2949669A1 (en) |
| ES (1) | ES8101613A1 (en) |
| FR (1) | FR2444043A1 (en) |
| GB (1) | GB2037772B (en) |
| IT (1) | IT1126572B (en) |
| NL (1) | NL7908988A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4591582A (en) * | 1984-04-17 | 1986-05-27 | Research Corporation | Organophosphorus compounds useful as anticonvulsant agents |
| IT1213182B (en) * | 1984-06-25 | 1989-12-14 | Simes | DERIVATIVES OF COMPOUNDS WITH A CATECOLAMINICAL STRUCTURE. |
| US4710566A (en) * | 1984-12-27 | 1987-12-01 | Yale University | Purification of the messenger RNA cap-binding protein |
| GB2289535B (en) * | 1994-05-13 | 1998-08-05 | Cambridge Life Sciences | Paracetamol phosphate for immunoassays |
| US5661138A (en) * | 1996-10-03 | 1997-08-26 | Clarion Pharmaceutical, Inc. | (o-Acyl-p-N-acylamino-phenyl)-O-phosphoethanolamines |
| US20110212926A1 (en) | 2008-05-20 | 2011-09-01 | Neurogesx, Inc. | Water-soluble acetaminophen analogs |
| EP2291084A4 (en) | 2008-05-20 | 2012-04-25 | Neurogesx Inc | Carbonate prodrugs and methods of using the same |
| WO2013044064A1 (en) | 2011-09-22 | 2013-03-28 | Neurogesx, Inc. | Acetaminophen conjugates, compositions and methods of use thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE296940C (en) * | 1911-08-02 | |||
| US2023551A (en) * | 1933-06-28 | 1935-12-10 | Rosenzweig Salo | Guaiacol compounds and the production thereof |
| US3032555A (en) * | 1955-11-03 | 1962-05-01 | Boots Pure Drug Co Ltd | Dichloroacetanilide esters and the manufacture thereof |
| US3107262A (en) * | 1962-01-25 | 1963-10-15 | Leo K Rochen | Alkyl acid phosphate salts |
-
1978
- 1978-12-15 FR FR7835429A patent/FR2444043A1/en active Granted
-
1979
- 1979-12-04 US US06/100,005 patent/US4322410A/en not_active Expired - Lifetime
- 1979-12-04 CH CH1073879A patent/CH642378A5/en not_active IP Right Cessation
- 1979-12-07 CA CA341,429A patent/CA1131627A/en not_active Expired
- 1979-12-07 IT IT28015/79A patent/IT1126572B/en active
- 1979-12-11 GB GB7942697A patent/GB2037772B/en not_active Expired
- 1979-12-11 DE DE19792949669 patent/DE2949669A1/en not_active Withdrawn
- 1979-12-13 NL NL7908988A patent/NL7908988A/en not_active Application Discontinuation
- 1979-12-14 JP JP16343479A patent/JPS5583792A/en active Pending
- 1979-12-14 ES ES486948A patent/ES8101613A1/en not_active Expired
- 1979-12-14 BE BE2/58269A patent/BE880615A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES486948A0 (en) | 1980-12-16 |
| DE2949669A1 (en) | 1980-07-03 |
| ES8101613A1 (en) | 1980-12-16 |
| FR2444043A1 (en) | 1980-07-11 |
| BE880615A (en) | 1980-06-16 |
| GB2037772A (en) | 1980-07-16 |
| FR2444043B1 (en) | 1981-07-24 |
| IT7928015A0 (en) | 1979-12-07 |
| JPS5583792A (en) | 1980-06-24 |
| NL7908988A (en) | 1980-06-17 |
| GB2037772B (en) | 1983-05-11 |
| IT1126572B (en) | 1986-05-21 |
| US4322410A (en) | 1982-03-30 |
| CA1131627A (en) | 1982-09-14 |
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Legal Events
| Date | Code | Title | Description |
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| PL | Patent ceased | ||
| PL | Patent ceased |